tbuckley/cabot-search huggingface dataset:
Serum vitamin D<sub>3</sub> levels and overall survival (OS) in patients (pts) with advanced biliary tract cancer (BTC): Analysis of the NIFTY trial cohort.
Authors: So Heun Lee, Jaekyung Cheon, Ilhwan Kim, Kyu-Pyo Kim, Baek-Yeol Ryoo, Jae Ho Jeong, Myoung Joo Kang, Byung Woog Kang, Hyewon Ryu, Ji Sung Lee, Changhoon Yoo
Journal: Journal of Clinical Oncology (2023)

613 Background: Although growing number of studies have explored the role of vitamin D 3 on various cancer types, no study has been conducted in the prospective cohort of advanced BTC. This analysis aimed to evaluate the predictive or prognostic implication of serum vitamin D 3 in pts with advanced BTC treated with second-line chemotherapy. Methods: The analysis is the preplanned subgroup analysis of the NIFTY trial, a multicenter, open-label, randomized, phase 2b study which compared the second-line liposomal irinotecan plus 5-FU/leucovorin and 5-FU/leucovorin in pts with advanced BTC. Serum vitamin D 3 (25-hydroxyvitamin D [25(OH)D]) levels were measured at baseline (i.e., C1D1) in a total of 176 pts out of 178 pts in the ITT population and were included in the current analysis. Correlation between OS and serum vitamin D 3 as a continuous variable was analyzed for linear and non-linear associations. Results: The median age was 64 years (range, 37–84) and 75 patients (42.6%) were women. The baseline serum vitamin D 3 levels ranged from 1.39 ng/ml to 140.02 ng/ml in the overall pts. There was no significant difference in the mean vitamin D 3 concentration according to the sex (male vs. female: 24.1 vs. 26.7; p=0.43), body mass index (BMI) (&lt;25 vs. 25-29.99 vs. ≥30: 24.0 vs. 30.0 vs 15.9; p=0.18), previous surgery (no vs. yes: 24.1 vs. 27.4; p=0.40), ECOG performance status (0 vs. 1: 24.1 vs. 25.5; p=0.66), and primary tumor site (intrahepatic vs. extrahepatic vs. gallbladder: 25.7 vs. 23.2 vs. 26.2; p=0.74). After adjustment for key prognostic factors including chemotherapy regimens, metastatic sites, or baseline CA 19-9 levels, there was no significant association between baseline serum vitamin D 3 and OS (HR=1.06 per 10 increase; 95% CI, 0.97–1.15; p=0.22). In addition, there was no non-linear association between vitamin D 3 and OS (p=0.52 for the linear model and p=0.62 for the model with restricted cubic splines). In the subgroup analysis, higher vitamin D3 levels were associated with poorer OS (HR=1.16 per 10 increase; 95% CI, 1.04–1.30; p=0.0072) in female pts. Conclusions: Serum vitamin D 3 levels did not show significant relationship with survival in pts with advanced BTC treated with second-line chemotherapy. High vitamin D 3 levels might be associated with poorer survival in female pts. Further larger studies are needed.
A retrospective study of circulating tumor DNA for minimal residual disease detection in the management of colorectal cancer.
Authors: Michael H. Storandt, Oluwadunni Eunice Emiloju, Tyler J. Zemla, Robert R. McWilliams, Frank A. Sinicrope, Jessica L. Mitchell, Qian Shi, Zhaohui Jin
Journal: Journal of Clinical Oncology (2023)

227 Background: Circulating tumor DNA (ctDNA) consists of small fragments of DNA released into the plasma from cancer cells. Tumor informed ctDNA testing by whole exome sequencing of the primary tumor coupled with multiplex polymerase chain reaction (PCR)-based next generation sequencing of cell free DNA in serum, can detect and quantify ctDNA, allowing for detection of minimal residual disease (MRD). Methods: We conducted a retrospective analysis of 120 patients with colorectal cancer who had at least one tumor-informed ctDNA MRD assay completed between May 6, 2019, and July 1, 2022, at Mayo Clinic, Rochester. Disease recurrence was defined as radiographic evidence consistent with recurrence with or without biopsy confirmation. Data are presented descriptively, including number of ctDNA assays completed, ctDNA positivity prior to disease recurrence, and ctDNA concordance with carcinoembryonic antigen (CEA). The study protocol was exempt after review by the Mayo Clinic Institutional Review Board. Results: One-hundred twenty patients were included in the study with median age at initial disease diagnosis of 67.0 years. Sixty-four percent were male and 94% were white. At time of initial diagnosis, 10 had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. In 120 patients, 476 ctDNA assays were performed, and 110 recurrences were observed among 62 patients. There were 39 instances in which ctDNA was obtained prior to clinical detection of recurrence and of these, at least one ctDNA assay was positive in 28 cases (72%). CEA was obtained prior to recurrence in 88 instances and was elevated in only 39 cases (44%). Among 37 instances where both ctDNA and CEA testing were obtained prior to recurrence, ctDNA was positive in 27 cases (73%) while CEA was positive in 14 cases (38%). ctDNA was positive in 83% of recurrences involving liver and 62.5% of recurrences involving only the lungs. ctDNA and CEA positivity are shown by location of recurrence. ctDNA and CEA were discordant in 44% of instances in which the assays were completed within 2-weeks of each other. Results of a ctDNA assay impacted management decisions in 16% of cases. Conclusions: ctDNA detected 72% of recurrences with higher rates of detection in liver versus lung metastasis. ctDNA performed superiorly to serum CEA in detection of recurrence, suggesting a role in disease surveillance. However, ctDNA impacted disease management in only 16% of patients, suggesting need for better patient selection and further study for ctDNA-based disease management strategy (more details will be reported). [Table: see text]
Effect of robot-assisted gastric ESD in difficult ESD locations.
Authors: Sang Hyun Kim, Bora Keum, Hyuk Soon Choi, Yoon Tae Jeen, Hoon Jai Chun
Journal: Journal of Clinical Oncology (2023)

355 Background: Since its introduction, endoscopic submucosal dissection (ESD) has become a standard treatment for early malignant lesions of stomach. However, ESD is technically demanding and it bears a high risk of complication for beginners. The difficulty of the ESD technique tends to depend on the location of the lesion. We compared and analyzed the efficacy of the ESD assistive robot that we developed in the location where stomach ESD is considered difficult. Methods: We have developed an automated simulator that can implement gastric ESD locations. An EndoGel (Sunarrow, Tokyo, Japan) was attached to the simulator to implement a virtual gastric location where ESD is difficult. "Difficult ESD locations" were selected in consideration of the location where a lot of muscle damage and frequent blind dissections occurred when conventional ESD was performed. An experienced endoscopist performed ten robot-assisted ESDs or conventional ESDs in 3 difficult and 3 easy positions, respectively. Results: While there was no significant difference in dissection speed of robot ESD and conventional ESD in easy positions, the submucosal dissection speed was remarkably faster in robotic ESD than in conventional ESD in difficult positions (P &lt; 0.05). In difficult positions, there was significantly more muscle damage in conventional ESD than in robotic ESD. (P &lt; 0.05). Conclusions: Dissection speed was greatly improved when assistive robots aided gastric ESD procedures in difficult locations. Our robotic device can thus provide simple, effective, and safe multidirectional traction during gastric ESD in difficult location.
Continuous maintenance (Maint) capecitabine (Cape) dosing for colorectal (CRC) and pancreatic cancers (PC): A single-institution, retrospective, real-world study.
Authors: Reetu Mukherji, Chao Yin, Benjamin Adam Weinberg, Ali Alqahtani, Rumaisa Hameed, Anna Barcellos, Maegan Connole, Chelsea Perelgut, Josephine Fortuin, John Marshall
Journal: Journal of Clinical Oncology (2023)

789 Background: Cape is an oral fluoropyrimidine (FP) used as maint therapy in CRC and PC. While the standard FDA dosing is 1250 mg/m 2 twice daily (BID) for 14 days followed by 7 days off in a 21-day cycle, there are variations across institutions as to the preferred schedule. To improve tolerability and convenience, our institution adopted a “continuous” dosing schedule where cape is taken BID Monday-Friday (M-F) with a treatment break on Saturday and Sunday. Here, we describe our institution’s experience with continuous maint dosing in advanced CRC and PC patients (pts) and explore real-world outcomes. Methods: Pts ≥ 18 years of age treated with continuous maint cape (+/- bevacizumab) after any line of therapy for stage 4 CRC/PC or locally advanced PC between 1/2016-12/2020 were identified in the COTA real-world database. The final study population included 35 PC and 85 CRC pts. Pt characteristics were analyzed descriptively and progression-free survival (PFS) was calculated using Kaplan Meier methods. Results: Among the 35 PC pts, the median age was 66 years (IQR: 61-73), 57.1% were females, and 65.7% were Caucasian. Among the 85 CRC pts, the median age was 54 years (IQR: 47-66), 47.1% were females, and 55.3% were Caucasian. Most PC (71.4%) and CRC (57.7%) pts were initially prescribed a total daily cape dose of 2 g (range 0.5-4 g). Dose adjustments, including dosage/schedule changes, occurred 11 times amongst PC and 36 times amongst CRC pts, and the leading cause was toxicity (72.7% in PC, 55.6% in CRC). Among PC pts, 14.3% had a dose reduction, 3% had a dose increase, and 11.4% switched to an alternative dosing schedule. Among CRC pts, these rates were 32.9%, 12.9%, and 9.4%, respectively. The leading cause of maint discontinuation was progression of disease (POD) (55.6% in PC, 59.3% in CRC). Additional outcomes are summarized in the table. Conclusions: Although maint FP is an established standard of care, it is often underutilized due to inherent inconveniences and toxicities associated with FDA cape dosing or intravenous FP therapy. The PFS reported here using a continuous cape dosing (predominantly starting at 2 g daily dosing) was in range with those previously reported in PC/CRC 1 st -line maint studies using FDA cape dosing or intravenous FP. The rates of cape discontinuation attributed to toxicity we report may be confounded by not controlling for the treatment setting. We argue fixed cape dosing (1 g BID) M-F should be considered a standard maint regimen based on efficacy, convenience, tolerability, and feasibility of dose adjustments.[Table: see text]
Identifying targeted therapy combination for refractory colorectal cancer using micro-organospheres.
Authors: Shengli Ding, Preeti Kanikarla Marie, Ray Zhang, Nicholas Baro, Daniel W Brown, Alan Bohn, Kelly Pittman, Marcin Paduch, Shiaowen David Hsu, Scott Kopetz, Xiling Shen
Journal: Journal of Clinical Oncology (2023)

27 Background: Metastatic colorectal cancer (CRC) patients who have become resistant to standard-of-care (SOC) treatments are often put on targeted therapies. However, patients with targeted mutations still often do not respond to the targeted therapies alone, hence it remains a critically unmet need to explore potential combinatorial regimens that will enhance the efficacy. Using micro-organospheres (MOS) derived from metastatic refractory patients who received targeted therapies, we performed a high-throughput combo screen and compared the response of these patient tumor avatars with their clinical responses. Methods: Biopsies from metastatic CRC patients who became resistant to SOC and were about to receive targeted therapies in clinical trials were molecularly profiled and implanted into immunodeficient mice to generate patient-derived xenografts (PDX). MOS were derived and established from PDX using droplet-based microfluidics for high-throughput 3D screening. Response of the MOS patient avatars to dose-titrated single and combination drug treatments including the available targeted therapies were measured by a fully automated robotic dispensing and imaging pipeline and quantified by AI-based live imaging analytical algorithm to generate drug response curves with IC50 and EC50. Results: MOS were successfully established in all PDX derived from refractory patients with targetable mutations including KRAS G12C and BRAF 600E as well as patients without targetable mutations. We tested both FDA-approved and experimental targeted therapies as single agent or in combination in 5-dose titrations. Longitudinal tracking of each MOS with Live/dead fluorescence dye signals was obtained for 5 days. MOS drug response curves and IC50s show correlation with clinical outcomes. Furthermore, this comprehensive dataset enabled us to assess the potential benefit of different combinations, help deconvolute the efficacy and synergy of individual drugs, and provide insight into patients who fail to response to targeted therapies despite possessing the targeted mutations. As the MOSdiagnostic assay can be completed from a patient biopsy within 10 days and is currently in a registered, multi-site clinical trial (ClinicalTrials.gov # NCT05189171), this study provides proof-of-principle for a potential clinical MOS-based assay to guide refractory patients to the optimal combination regimen. Conclusions: Refractory patients may benefit from a MOS-based high-throughput screen assay to select the optimal combination regimen containing targeted therapy.
Etiologies of cirrhosis by ethnicities of patients with hepatocellular carcinoma.
Authors: Jeremy Chang, Veeral Ajmera, Kathryn J Fowler, Adam Burgoyne
Journal: Journal of Clinical Oncology (2023)

515 Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. While there are several factors that can impact patient outcomes, ethnicity remains a major contributor towards disease incidence and the expected clinical course. There are various etiologies that can lead to the development of HCC among different ethnic groups, though further studies are required to identify the most pertinent risk factors in recent years. Methods: This was a single center, retrospective study in HCC patients to identify differences in cirrhosis etiologies based on ethnicity. All patients were diagnosed with HCC between March 2014 and April 2022. Possible causes of cirrhosis included alcohol, hepatitis B virus (HBV), hepatitis C virus (HCV), nonalcoholic fatty liver disease (NAFLD), and other chronic liver disease. Results: A total of 276 patients were included in this study. For ethnic background, there were 97 Latino, 97 White, 50 Asian, 16 Black, and 16 patients of other ethnicities. With regards to significant differences in the etiologies of cirrhosis, 58 patients (59.8%) of White ethnicity were found to have cirrhosis related to HCV compared to 71 patients (39.7%) of all other ethnic groups (p = 0.002). In addition, when comparing Latino to non-Latino patients, there was a greater proportion of patients with cirrhosis due to NAFLD (24.7% vs 10.1%, p = 0.002) and cirrhosis from alcohol consumption (24.7% vs 10.1%, p = 0.002). HBV also varied significantly by ethnicity with 16 Asian patients (32%) found to have HBV cirrhosis compared to 5 patients (2.2%) of other ethnic groups (p &lt;0.001). See table for additional details. Conclusions: Our study demonstrates significant differences in the cirrhosis etiologies of HCC patients depending on ethnicity. With the incidence and mortality rates of HCC continuing to rise worldwide, it is important for clinicians to be aware of these differences so that the appropriate preventative measures can be pursued.[Table: see text]
Anlotinib plus toripalimab as first-line treatment for patients with unresectable hepatocellular carcinoma: Updated results of the ALTER-H003 trial.
Authors: Haifeng Lin, Jie Ma, Manyun Zhuo, Chengsheng Zhang, Jingru Luo, Xiaohong Zhuang, Zhiming Zeng, Lihua Yang
Journal: Journal of Clinical Oncology (2023)

568 Background: Anti-angiogenic plus anti-PD-1/L1 agents have shown superior efficacy over sorafenib in the first-line treatment for uHCC. Anlotinib, a multi-targeted tyrosine kinase inhibitor that targets VEGFR 1/2/3, FGFR 1-4, PDGFR α and β, and c-kit. Toripalimab is a humanized lgG4 mAb against PD-1. Preliminary results exhibited promising efficacy and tolerable safety of the combined regimen. Here we reported the updated results at the data cutoff of August 24, 2022. Methods: This single arm, multicenter, phase II trial of ALTER-H003 was planned to enroll 30 eligible pts to receive anlotinib (12mg, p.o., qd, d1-14, q3w) and toripalimab (240mg, iv, d1, q3w) until disease progression or unacceptable toxicity. Primary endpoint was ORR. Secondary endpoints included PFS, OS, DCR, DoR and safety. Results: From Jan, 2020 to Jul, 2021, 31 pts were enrolled. Pts characteristics were as follows: median age of 56y (range: 27-75); hepatitis B (29, 93.5%); BCLC B/C (23, 74.2%/8, 25.8%); macrovascular invasion (11, 35.5%); extrahepatic metastasis (19, 61.3%) and AFP&gt;400 ng/ml (12, 38.7%). The median follow-up time was 19.9m (95%CI: 14.3–25.5). The confirmed ORR and DCR by mRECIST was 32.3% (95%CI: 14.8-49.7%) and 77.4% (95%CI: 61.8-93.0%), respectively. 10 pts achieved tumor response and the mDOR was 11.1m. The median PFS was 11.0m (95%CI: 3.5-18.4) and the median OS was 18.2m (95%CI: 15.9-20.5). Grade 3-5 treatment-related adverse events (TRAEs) were recorded in 20 pts (64.5%). The common ≥ grade 3 TRAEs included hand-foot skin reaction (3, 9.7%), hypertension (3, 9.7%) and impaired liver function (3, 9.7%). 2 pts had an irTRAE (pneumonitis; impaired liver function) that led to death. Conclusions: Anlotinib plus toripalimab showed hopeful efficacy and manageable toxicity in the first-line treatment for uHCC. Further studies are warranted. Clinical trial information: ChiCTR1900028295 .
Phase 2 multi-institutional prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged 80 years or more after curative resection of colorectal cancer: The HiSCO-03 study.
Authors: Masashi Miguchi, Satoshi Ikeda, Manabu Shimomura, Masahiro Nakahara, Tomohiro Adachi, Yasuyo Ishizaki, Yasufumi Saitoh, Kazuhiro Toyota, Daisuke Sumitani, Yosuke Shimizu, Yuji Takakura, Wataru Shimizu, Masanori Yoshimitsu, Shinya Kodama, Masahiko Fujimori, Mamoru Oeda, Hironori Kobayashi, Hideki Ohdan
Journal: Journal of Clinical Oncology (2023)

101 Background: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥80 years who underwent curative resection. We conducted a prospective phase II feasibility study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. Methods: This study involved 15 institutions of the Hiroshima Surgical Oncology Study Group (HiSCO). Patients with stage III CRC aged ≥80 years who underwent curative resection with an Eastern Cooperative Oncology Group performance status of 0–1 were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m 2 per day as tegafur; LV, 75 mg/day on days 1–28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. Results: Sixty-nine patients were enrolled in the study between December 2013 and June 2021. Of the 69 patients, 65 were included in the analysis, excluding two ineligible patients and two who discontinued before treatment commenced. There were 32 males and 33 females with a median age of 82 years (range, 80–88 years). There were four patients with stage IIIA CRC, 49 with stage IIIB, and 12 with stage IIIC. In the primary endpoint, administration completion rate was 67.3% (95% confidence interval: 54.9The median relative dose intensities were 84% (range, 4–100%) for UFT, and 100% (range, 4–100%) for LV. Incidence of grade three or higher adverse events were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). No treatment-related deaths occurred. An independent risk factor was not identified in the background risk factor analysis for treatment discontinuation. Conclusions: Uracil-tegafur and leucovorin are not recommended as standard adjuvant therapy for patients with stage III CRC ≥80 years of age because of the possibility of lower completion rates. The frequency of serious adverse events was acceptable, and safety was confirmed in the treated patients. It is necessary to clarify the background of patients in which administration is discontinued and to investigate the impact on long-term prognosis. Clinical trial information: R000013902 .
Metachronous colorectal cancers in Icelandic MSH6 and PMS2 Lynch syndrome carriers in 1955-2017: A population-based study.
Authors: Sigurdis Haraldsdottir, Arna Kristin Andresdottir, Haukur Einarsson, Hildur Jonsdottir, Petur Snaebjornsson, Einar Stefan Bjornsson, Jon G. Jonasson
Journal: Journal of Clinical Oncology (2023)

76 Background: The prevalence of Lynch syndrome in Iceland is the highest described so far or 1:226 with three founder mutations, one in MSH6 and two in PMS2, and was first reported in 2017. Lynch syndrome predisposes carriers to colorectal cancer and metachronous primaries. Most data on metachronous colorectal cancer reflects on MLH1 and MSH2 carriers and is not well described in MSH6 and PMS2 carriers. The purpose of this study was to examine the cumulative incidence of metachronous colorectal cancer in Icelandic Lynch syndrome carriers diagnosed with colorectal cancer from 1955-2017. Methods: This retrospective study included all individuals with pathogenic variants in mismatch repair genes identified in a nationwide genotype database and a colorectal cancer diagnosis in the Icelandic Cancer Registry from 1955-2017. DeCODE genetics has collected extensive genotypic information on the Icelandic population sequencing the whole genomes of 49,708 Icelanders and imputing genotypes into 116,573 Icelanders whose DNA had been genotyped with SNP chips. Cancer information was obtained from patient charts and cause of death obtained from the Cause of Death Register. All polyp pathology was accessed in the pathology registry and reassessed by two pathologists. Results: A total of 65 individuals developed colorectal cancer during the study period with 34 (52.3%) PMS2 carriers and 25 (38.5%) MSH6 carriers. The cumulative incidence of metachronous colorectal cancer was low or one case (1.5%) in an MSH2 carrier with a median follow-up time of 58 months (Q1 8.0, Q3 167.0, range 0-365 months) in the cohort. Only two (3.1%) individuals, one with MSH2 and one with MSH6 pathogenic variants, underwent a total colectomy. Median age at first colorectal cancer diagnosis was 63 years (Q1 54.0, Q3 72.5, range 28-94). Thirty-one (47.7%) individuals had polyps resected during the study period with adenomas (67.1%) being the most common. Significantly more MSH6 carriers had a history of advanced adenomas as compared to PMS2 carriers (36.0 % vs 11.8%, p = 0.026). Five-year colorectal cancer survival was 81.4% for PMS2 carriers and 71.5% for MSH6 carriers. Conclusions: The incidence of metachronous colorectal cancer was zero in Lynch syndrome carriers with MSH6 or PMS2 pathogenic variants from 1955-2017 despite these individuals not undergoing rigorous Lynch syndrome screening. This would support performing segmental colectomies and following European screening guidelines for MSH6 and PMS2 carriers in Iceland.